Process for the production of citalopram

ABSTRACT

The invention relates to a process for the manufacture of salts of citalopram in high purity. By the careful selection of solvents and the careful manipulation of the pH value, citalopram salts may be isolated in the absence of 5-chlorocitalopram, 5-bromocitalo-pram, desmethyl-citalopram and 5-carobxyamide citalopram.

This invention relates to citalopram, in particular salts of citalopramand a process for the manufacture of said salts in very high purity.

Citalopram is a well-known anti-depressant drug which has been on themarket for a number of years. It has the structure shown below.

Citalopram is a selective, centrally acting serotonin(5-hydroxytryptamine:5-HT) re-uptake inhibitor and accordingly possessesanti-depressant activity. The anti-depressant activity of the compoundhas been reported in a number of publications and citalopram has furtherbeen disclosed as showing potential in the treatment of dementia andcerebrovascular disorders.

Citalopram was first disclosed in U.S. Pat. No. 4,136,193 whichdescribes a number of processes for its preparation. Once manufactured,the citalopram base is generally converted to a salt using conventionalprocedures although it can be used as a free base. Hydrobromide saltsare especially preferred since they are orally available.

Since the publication of the above mentioned U.S. Patent, a number offurther processes for the preparation of citalopram have been devisedand in many of these, as well as in the above U.S. Patent, the last stepof the process involves the conversion of a group different from thecyano in the 5 position of the phthalane ring into the 5-cyano group.Preferably the conversion takes place from a bromine analogue.

As is well-known however, impurities are inevitably formed during thecyanation reaction and these impurities are difficult to separate fromthe desired end product. Impurities also remain from early synthesisstages and accordingly, extensive purification procedures are required.

Where the final stage of citalopram manufacture involves cyanation of5-bromine analogue to the corresponding nitrile, the main impuritiesencountered are:

Various purification procedures are already known in the art forpurifying a crude citalopram mixture produced after such a cyanationreaction. For example, GB 2356199 teaches that the impurities may beremoved using a conventional film distillation technique. The crude baseis simply distilled using, for example, a thin film distillationapparatus yielding a purer citalopram material. The base product maythen be formed into the salt. GB 2357762 describes an alternativeprocedure in which the crude free base is simply crystallised prior toconversion to the salt.

There still remains the need however, to devise efficient and moreeconomic purifycation procedures especially for use on industrial scalewhere, for example, the use of film distillation apparatus may beprohibitively expensive.

The present inventors have now found an alternative and rapid way ofisolating purer citalopram salts substantially in the absence of theabove-mentioned impurities without using potentially time consumingcrystallisation techniques or expensive film distillation apparatus.Rather, the present inventors have found that by the careful selectionof solvents and the careful manipulation of pH, citalopram salts may beisolated in very high purity in the absence of the major impurities5-chlorocitalopram, 5-bromocitalopram, desmethyl-citalopram and5-carboxyamide citalopram.

Thus, viewed from one aspect the invention provides a process for thepreparation of a salt of citalopram comprising:

-   (A) dissolving citalopram in a solvent selected from acetone,    alcohol, or toluene or mixtures thereof and adding oxalic acid;-   (B) separating the precipitated citalopram oxalate, e.g. by    filtration;-   (C) suspending said citalopram oxalate in water and adding a base in    an amount sufficient to liberate citalopram, e.g. to a pH 9 to 10;-   (D) extracting the liberated citalopram with an organic solvent,    isolating the organic phase and evaporating said solvent;-   optionally repeating steps (A) to (D),-   repeating steps (A) and (B) and subsequently;-   (E) suspending said citalopram oxalate in water and adding base to a    pH 6 to 7;-   (F) adding a solvent selected from toluene, cyclohexane, n-hexane,    n-heptane, isopropyl ether or xylene or mixtures thereof and    isolating the aqueous phase;-   (G) adding base to said aqueous phase in an amount sufficient to    liberate citalopram and extracting the liberated citalopram with an    organic solvent, isolating the organic phase and evaporating said    solvent;-   (H) dissolving said citalopram in an alcohol solvent, adding an acid    and separating the precipitated citalopram salt.

Viewed from another aspect the invention comprises a process for theseparation of desmethyl citalopram from a crude mixture thereof withcitalopram base comprising:

-   (A) dissolving citalopram in a solvent selected from acetone,    alcohol, or toluene or mixtures thereof and adding oxalic acid;-   (B) separating the precipitated citalopram oxalate;-   (C) suspending said citalopram oxalate in water and adding a base in    an amount sufficient to liberate citalopram, e.g. to a pH 9 to 10;-   (D) extracting the liberated citalopram with an organic solvent,    isolating the organic phase and evaporating said solvent;-   optionally repeating steps (A) to (D).

Viewed from a still further aspect the invention provides a process forthe separation of 5-chlorocitalopram and 5-bromocitalopram from a crudemixture of citalopram oxalate comprising:

-   (E) suspending citalopram oxalate in water and adding base to a pH 6    to 7;-   (F) adding a solvent selected from toluene, cyclohexane, n-hexane,    n-heptane, isopropyl ether or xylene or mixtures thereof and    isolating the aqueous phase.

Viewed from another aspect the invention provides a process for theseparation of 5-carboxyamide from a crude mixture of citalopramcomprising:

-   (H) dissolving citalopram in an alcohol solvent, adding an acid and    separating the precipitated salt, e.g. by filtration.

Viewed from a still yet further aspect the invention provides citalopramor salts thereof obtained by the processes of the invention as well astheir use in medicine and pharmaceutical salts comprising the same.

As used herein “citalopram” refers to the free base thereof.

In part (A) of the process of the invention, the crude citalopram baseshould preferably be dissolved in acetone. Without wishing to be limitedby theory, it is believed that desmethyl citalopram is removed in thesolvent washings in step (B) when the citalopram oxalate salt isisolated. It has been found that the most efficient elimination ofdesmethyl citalopram occurs when the solvent employed is acetone.

Isolation of the precipitated citalopram oxalate in step (B) may beachieved by, for example, filtration or centrifugation or by any otherconventional technique for separating a solid from a liquid. Thecitalopram oxalate is precipitated (it being insoluble in the organicsolvent employed) and isolation should not be effected by evaporatingoff the organic phase since the desmethyl citalopram would, of course,not be removed in such a procedure.

The base used to liberate citalopram from its oxalate in step (C) may beany conventional base which is compatible with citalopram. Suitablebases include NaOH, KOH and various organic bases however, it ispreferred if ammonia is used as the base. The pH of the solution in step(C) needs to be increased to a value sufficient to ensure citaloprambase is liberated and the required pH will be readily determined by theskilled chemist. It is preferred however if the pH is adjusted tobetween 8.5 to 10, especially, 9.0 to 9.5, most preferably 9.0 to 9.2.The pH can of course be monitored using standard indicators or other pHmeasuring apparatus.

The liberated citalopram free base may be extracted from the aqueoussolution by using a standard organic solvent (Step D). Most suitable inthis regard is toluene although other hydrocarbon solvents such asxylene, hexane, heptane etc. could be employed equally successfully. Theorganic phase formed should be separated by a simple layer separationprocedure and the solvent may then be evaporated off by simpledistillation or under reduced pressure. Conveniently however, thesolvent is removed under atmospheric pressure conditions so as tomaintain the liberated citalopram as an oil. By using atmosphericpressure evaporation, it is likely that some traces of solvent willremain (perhaps up to 10%) hence maintaining the liberated citalopram inan oil form.

In order to remove any remaining traces of desmethyl citalopram it maybe necessary to repeat the oxalate formation and subsequent baseliberation steps (A to D).

Without wishing to be limited by theory, it is believed that the furthermain impurities, bromo/chloro citalopram can be removed by carefulmanipulation of pH and then by washing in particular solvents.

In order to remove these impurities according to the invention, it isnecessary to add citalopram oxalate to water and adjust the pH of thesolution to 6 to 7, preferably 6.2 to 7 (Step E). Again the base may beany base suitable for this task, e.g. as described above in relation tostep (C), however, ammonia is again preferred.

The inventors have surprisingly found that at this pH citalopram oxalateremains substantially in its salt form but the salts of the chloro andbromo intermediates tend to convert back to their corresponding bases.On organic washing therefore (Step F), it has surprisingly provedpossible to remove the impurities in the organic washings whilstmaintaining the desired product in the aqueous phase. The organicwashing solvent is conveniently toluene, cyclohexane, n-hexane,n-heptane, isopropyl ether or xylene or mixtures thereof. In a preferredembodiment the solvent is toluene, cyclohexane or a mixture thereof.

After the impurities have been removed in the organic phase, the aqueouslayer can then be fully basified and the citalopram free base extractedinto an organic solvent for subsequent conversion to the desiredcitalopram salt (Step G). Again, the solvent used to extract theliberated citalopram can be any solvent suitable for the task, e.g.those described above with respect to step (D).

Most suitable in this regard is again toluene although other hydrocarbonsolvents such as xylene, hexane, heptane etc could be employed equallysuccessfully. The solvent may then be evaporated off by simpledistillation or under reduced pressure. Conveniently however, thesolvent is removed under atmospheric pressure conditions so as tomaintain the liberated citalopram as an oil. By using atmosphericpressure evaporation, it is likely that some traces of solvent willremain (perhaps up to 10%) hence maintaining the liberated citalopram inan oil form.

It is during the final stage, i.e. conversion to the desired salt, thatthe inventors believe that the 5-carboxyamide citalopram impurity may beremoved.

This is achieved by dissolving the citalopram in an alcohol solvent,especially isopropyl alcohol or methanol. The aqueous salt formingagent, i.e. acid, is then added to form the citalopram salt (Step H).The citalopram salt crystals may be isolated conventionally byfiltration or centrifugation but the 5-carboxyamide citalopram impurityremains in the organic phase and is hence easily and surprisinglyremoved with the organic phase.

The salt to be manufactured is preferably the hydrobromide,hydrochloride or oxalate salt.

The purification technique of the present invention is particularlysuitable for preparing citalopram hydrobromide where the initialcitalopram mixture has been prepared via a cyanation of5-bromocitalopram. However, the process is equally suitable for thepurification of the crude citalopram made by any other process. Othersuch processes are described in, for example, EP-A-171943.

The cyanation of bromocitalopram is easily carried out using, forexample, sodium cyanide or preferably copper cyanide. Bromocitalopramitself can be manufactured in a number of ways, for example, asdescribed in U.S. Pat. No. 4,136,193.

Depending on the nature of the impurities present it may be possible toomit some of the purification stages of the process of the invention.Thus, if no desmethyl citalopram is present in a crude citaloprammixture, it may be possible to omit stages (A) to (D) and simply removethe other impurities following the teaching of steps (E) to (H). Thisforms a further aspect of the invention. Similarly, if a 5-carboxyamidecitalopram impurity is not present then conversion to the desired saltmay be effected without following the explicit teachings of step (H).Hence the present invention also provides a process as described insteps (A) to (G) and steps (A) to (D) followed by step (H).

Citalopram salts made by the process of the invention may be formulatedinto pharmaceutical compositions as is well known in the art. Suchcompositions may take the form of tablets which may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tabletingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatin, lactose, gums and is thelike. Any other adjuvant or additive colourings, aroma, preservatives,taste masking agents etc. may be used provided that they are compatiblewith the active ingredient.

The active ingredient may also be formulated as a solution for injectionwhich may be prepared by solving the active ingredient and possibleadditives in a part of the solvent for injection, preferably sterilewater, adjusting the solution to the desired volume, sterilisation ofthe solution and filling in suitable ampoules or vials. Again, anysuitable additive conventionally used in the art may be added such astonicity agents, preservatives, antioxidants, etc.

The amount of citalopram administered to a patient is dependent on thenature of the patient and will be readily determined by the skilledphysician. Tablets may however comprise, for example, 20 mg or 40 mgdoses.

Citalopram may be administered along with any other pharmaceutical withwhich it is compatible and additional active ingredients can of coursebe formulated into compositions with citalopram as is well known in theart.

The invention will now be further described with reference to thefollowing non-limiting examples.

EXAMPLE 1 1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3dihydrobenzofuran-5-carbonitrile oxalate (Citalopram Oxalate)

Citalopram was prepared substantially as described in Example 2 of U.S.Pat. No. 4,136,193 although toluene was used instead of benzene. 100 gof citalopram (0.30 mol) with a desmethyl citalopram content of up to5.0% was added to acetone (300 ml) and the resulting solution stirredfor 15 min. at 40° C. To the above clear solution was added oxalic acid(40 g, 0.31 mol), dissolved in acetone (300 ml) and the resultingmixture heated to 50-55° C. The mixture was cooled and the whitecrystals of the title compound were filtered off at room temperature anddried at 60° C. for 6 hrs at atmospheric pressure.

Citalopram oxalate prepared as in Example 1 (105 g, 0.25 mol) wassuspended in water (525 ml) and the pH was adjusted to 9.0-9.2 by theaddition of ammonia. The mixture was stirred for 30 minutes andextracted with toluene twice (250 ml). The organic phases were separatedand washed with water (100 ml). Toluene layer was concentrated undervacuum. Acetone (300 ml) is added to the residue and the mixture stirredfor 15 min. at 40° C. To the above clear solution was added oxalic acid(33 g, 0.26 mol), dissolved in Acetone (300 ml) and the mixture washeated to 50-55° C. The white crystals of the title compound werefiltered off at room temperature and dried at 60° C. for 6 hrs atatmospheric pressure.

Yield: 90 g (85%). Desmethyl citalopram content less than 0.1%.

EXAMPLE 2 1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3dihydrobenzofuran-5-carbonitrile hydrobromide (Citalopramhydrobromide)

1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydrobenzofuran-5-carbonitrileoxalate (90 g, 0.21 mol) prepared as per example 1 was suspended inwater (500 ml) and aqueous ammonia (20-25%) was added to adjust the pHof the solution to 6.2-7.0 (approximately 20 ml). The solution isstirred for 15 min. The above solution was washed with toluene (6×50 ml)and the organic phases are separated. To the remaining aqueous phase wasadded ammonia (20-25%) to bring the pH to 9.0-9.2. The mixture wasstirred for 15 min, and extracted with toluene (2×250 ml). The organicphases were washed with NaCl solution (100 ml, 10%) and the tolueneremoved in vacuum to leave an oily residue. To the residue was added 350ml isopropylalcohol and the clear solution filtered through Celite®. Tothe resulting clear solution is added 35 g of 48% aq. hydrobromic acidand the mixture is stirred for 1 hr at 50° C. After cooling to 20° C.,the crystals are filtered and dried.

Yield: 75 g (85%) Purity: 99.7%

1. A process for the preparation of a salt of citalopram comprising: (A)dissolving citalopram in a solvent selected from acetone, alcohol, ortoluene or mixtures thereof and adding oxalic acid; (B) separating theprecipitated citalopram oxalate; (C) suspending said citalopram oxalatein water and adding a base in an amount sufficient to liberatecitalopram; (D) extracting the liberated citalopram with an organicsolvent, isolating the organic phase and evaporating said solvent;optionally repeating steps (A) to (D), repeating steps (A) and (B) andsubsequently; (E) suspending said citalopram oxalate in water and addingbase to a pH 6 to 7; (F) adding a solvent selected from toluene,cyclohexane, n-hexane, n-heptane, isopropyl ether or xylene or mixturesthereof and isolating the aqueous phase; (G) adding base to said aqueousphase in an amount sufficient to liberate citalopram and extracting theliberated citalopram with an organic solvent, isolating the organicphase and evaporating said solvent; (H) dissolving said citalopram in analcohol solvent, adding an acid and separating the precipitatedcitalopram salt.
 2. A process for the separation of desmethyl citalopramfrom a crude mixture thereof with citalopram base comprising: (A)dissolving citalopram in a solvent selected from acetone, alcohol, ortoluene or mixtures thereof and adding oxalic acid; (B) separating theprecipitated citalopram oxalate; (C) suspending said citalopram oxalatein water and adding a base in an amount sufficient to liberatecitalopram; (D) extracting the liberated citalopram with an organicsolvent, isolating the organic phase and evaporating said solvent;optionally repeating steps (A) to (D).
 3. A process for the separationof 5-chlorocitalopram and 5-bromocitalopram from a crude mixture ofcitalopram oxalate comprising: (E) suspending citalopram oxalate inwater and adding base to a pH 6 to 7; (F) adding a solvent selected fromtoluene, cyclohexane, n-hexane, n-heptane, isopropyl ether or xylene ormixtures thereof and isolating the aqueous phase.
 4. A process for theseparation of 5-carboxyamide from a crude mixture of citalopramcomprising: (H) dissolving citalopram in an alcohol solvent, adding anacid and separating the precipitated salt.